Cells respond to heat and other environmental stresses by expressing inducible heat shock proteins. The most prominent and best characterized of the stress proteins is the Hsp70 family of proteins which encompasses a group of at least eleven highly related proteins, the major protein of which, in humans, is designated Hsp72.
The various Hsp70 isoforms are encoded by a multigene family of genes. The Hsp70 proteins are highly conserved ATP binding proteins present in all cell types and distributed throughout all cellular compartments. Hsp70 and the chaperone protein DnaI function together in a complex to carry out a number of biochemical activities. Such activities include nascent protein folding, protein translocation across the endoplasmic reticulum, and prevention of protein aggregation. The heat shock proteins also associate with denatured or partially unfolded proteins, protecting them from further denaturation and assisting in their refolding. (Tavaria, M. et al., 1996, Cell Stress & Chaperones 1:23-28). The release of “processed” proteins is mediated by ATP.
Hsp70 has been shown to intervene in the apoptotic process. For example, the transfection of the Hsp70 gene into cells protects those cells from cell death induced by TNF-α (Jaattela, M., 1992, EMBO J. 11:3507-3512). Furthermore, pretreatment of tumor cells with Hsp70 antisense oligomer enhanced quercetin-induced apoptosis (Wei, Y., 1994, Cancer Res. 54:4952-4957).
Levels of Hsp72 have been demonstrated to be increased in the majority of tumor cells (Li et al., 1995, Int. J. Hyperthermia 11:459-488). In some instances, such as breast cancer, the level of Hsp72 serves as a positive prognostic marker, and, in some patients, the only independent predictor of disease reoccurrence (Ciocca et al., 1993, Natl. Cancer Inst. 85:570-574). In addition, overexpression of Hsp70 in mouse fibrosarcoma cells (WEHI-S) conferred tumorigenicity in syngenic mice (Jaattela, M., 1995, Int. J. Cancer 60:689-693). In transgenic mice, constitutive expression of Hsp72 in T lymphocytes coincides with a greatly increased incidence of generalized malignant lymphoma (Seo et al., 1996, Biochem. Biophys. Res. Commun. 218:582-587).